Vagus nerve stimulation method

ABSTRACT

An implanted electrical signal generator delivers a novel exogenous electrical signal to a vagus nerve of a patient. The vagus nerve conducts action potentials originating in the heart and lungs to various structures of the brain, thereby eliciting a vagal evoked potential in those structures. The exogenous electrical signal simulates and/or augments the endogenous afferent activity originating from the heart and/or lungs of the patient, thereby enhancing the vagal evoked potential in the various structures of the brain. The exogenous electrical signal includes a series of electrical pulses organized or patterned into a series of microbursts including 2 to 20 pulses each. No pulses are sent between the microbursts. Each of the microbursts may be synchronized with the QRS wave portion of an ECG. The enhanced vagal evoked potential in the various structures of the brain may be used to treat various medical conditions including epilepsy and depression.

CROSS REFERENCE TO RELATED APPLICATION(S)

This application claims the benefit of U.S. Provisional Application No.60/787,680, filed Mar. 29, 2006.

The United States patent application entitled “Synchronization Of VagusNerve Stimulation With The Cardiac Cycle Of A Patient” by Arthur D.Craig and filed concurrently herewith is hereby incorporated herein byreference.

The U.S. patent application entitled “Microburst Electrical StimulationOf Cranial Nerves For The Treatment Of Medical Conditions,” by Arthur D.Craig and filed concurrently herewith is hereby incorporated herein byreference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention is directed generally to neurostimulation of thevagus nerve, and more particularly to an improved apparatus and methodfor vagus nerve stimulation therapy using heart rate variabilitysynchronization, patterned electrical pulses inside a pulse burst, andelectroencephalogram (“EEG”) based optimization.

2. Description of the Related Art

Vagus nerve stimulation (“VNS”) (for example, VNS Therapy™ byCyberonics, Inc.) is an FDA-approved method for alleviatingtreatment-resistant epilepsy and depression.

Vagus nerve stimulation was initially developed and approved by the FDAfor the treatment of refractory partial onset epilepsy. Recently, it hasbeen reported that the use of VNS in human patients with epilepsy isassociated with an improvement in mood. As a consequence, VNS has alsobeen approved as a treatment for refractory depression (treatmentresistant depression).

VNS typically involves implanting a nerve stimulating electrode on theleft or right vagus nerve in the neck. The electrode is connected to asubcutaneous pacemaker-like control unit that generates an electricalnerve stimulating signal. A Vagus Nerve Stimulator (“VNS stimulator”) isan example of an implantable stopwatch-sized, pacemaker-like controlunit device configured to electrically stimulate the vagus nerve leadingto the brain.

Conventional VNS is generally applied every 5 minutes in a 7 second toone minute burst (see FIG. 3A for a portion of an exemplary burst)including a pulse train of uniformly spaced apart pulses having a pulsecurrent amplitude of about 0.5 mA to about 2.0 mA). The pulses aredelivered at about 20 Hz to about 50 Hz. Each of the pulses may have awidth of about 0.5 milliseconds. VNS is currently approved to treatepileptic seizures and depression when drugs have been ineffective.

Consequently, a need exists for methods of delivering electricalstimulation to the vagus nerve. Further, a need exists for improvedelectrical signals that increase the efficacy of VNS.

SUMMARY OF THE INVENTION

In one embodiment, the invention includes a method of treating a medicalcondition by detecting a portion of the QRS wave of the patient'scardiac signal and after detecting the portion of the QRS wave,delivering a microburst comprising 2 to 20 electrical pulses to thepatient's vagus nerve. Each of the microbursts may have duration of lessthan about 100 milliseconds. In particular embodiments, the interpulseintervals separating the pulses are about 3 milliseconds to about 12milliseconds. In alternate embodiments, the interpulse intervals areless than about 40 milliseconds. In various embodiments, the sum of theinterpulse intervals is less than about 40 milliseconds, and in furtherembodiments, less than about 60 milliseconds. In further embodiments,the method includes waiting a predetermined delay period after thedetection of the portion of the QRS wave before generating themicroburst.

In another embodiment, the invention includes an exogenous electricalsignal delivered to a patient's vagus nerve and adapted to treat amedical condition present in the patient by enhancing the vagal evokedpotential in the patient's brain. The exogenous electrical signalincludes a series of microbursts each having about 2 to about 20electrical pulses. In some embodiments, the exogenous electrical signalincludes a series of microbursts each having a duration less than aboutone second. The invention also includes an implantable device configuredto apply the inventive exogenous electrical signal.

In further embodiments, the microbursts of the exogenous electricalsignal may be synchronized with the R wave portion of the patient'scardiac cycle. In particular embodiments, each of the microbursts of theexogenous electrical signal occur after a selected R wave portion. Invarious embodiments, each of the microbursts occurs less than about 1000milliseconds after the selected R wave portion. The pulses of themicrobursts may be spaced to simulate the endogenous afferent activityoccurring at a particular time in the cardiac cycle. Further, each ofthe microbursts may be delayed relative to the selected R wave portionto simulate the endogenous afferent activity occurring at a particulartime in the cardiac cycle. In various embodiments, the delay has aduration less than about 500 milliseconds. In further embodiments, thedelay has a duration less than about 1000 milliseconds.

In various embodiments, each of the microbursts occurs after an R-Rinterval (i.e., the amount of time between two successive R waveportions in the cardiac signal) having a duration that is shorter thanthe duration of the previous R-R interval. In further embodiments, themicrobursts are delivered to the vagus nerve after the R wave portionsoccurring during inspiration but not after the R wave portions occurringduring expiration.

The invention also includes a method of customizing the exogenouselectrical signal to elicit a desired vagal evoked potential in aselected structure of the brain associated with a medical condition. Themethod includes determining a value of a signal parameter (e.g., pulsewidth, pulse frequency, an interpulse interval between two of the pulsesof the microburst, microburst frequency, a number of microbursts of theseries of microburst, a duration of the electrical signal, a number ofpulses in the microbursts, etc.), generating an electrical signal havinga series of microbursts of 2 to 20 electrical pulses each according tothe signal parameter, delivering the electrical signal to the patient'svagus nerve, analyzing an EEG of the patient's brain created during thedelivery of the electrical signal to determine the vagal evokedpotential observed in the selected structure of the brain, and modifyingthe value of the signal parameter based on the vagal evoked potentialobserved in the selected structure of the brain to modify the vagalevoked potential observed therein. In various embodiments, the selectedstructure of the brain includes the thalamus, striatum, and/or insularcortex.

Embodiments of the invention also include a computer readable mediumhaving computer executable components for detecting the QRS wave portionof the cardiac cycle, generating a microburst, and delivering themicroburst to the vagus nerve of a patient in response to the detectionof the QRS wave portion of the patient's cardiac cycle.

The invention also includes embodiments wherein the patient manuallytriggers the generation and delivery of the inventive exogenouselectrical signal to his/her vagus nerve.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING(S)

FIG. 1 illustrates a portion of an ECG trace located above a portion ofa trace illustrating an exogenous electrical signal patterned intomicrobursts that are synchronized with the QRS wave portion of the ECGtrace. Each of the microbursts begins after a delay period following theQRS wave portion of the ECG trace.

FIG. 2A illustrates a conventional electrical signal generator that maybe modified to deliver an exogenous electrical signal constructedaccording to the present invention.

FIG. 2B is a block diagram illustrating various components of theelectrical signal generator of FIG. 2A.

FIG. 3A is a trace illustrating an exemplary conventional VNS exogenouselectrical signal having a series of pulses.

FIG. 3B is a trace of the potential measured in a monkey's thalamuswhile a portion of the conventional pulse burst of FIG. 3A was appliedto the vagus nerve of the monkey.

FIG. 3C is a trace illustrating an exemplary embodiment of an exogenouselectrical signal constructed according to the present invention.

FIG. 3D is a trace illustrating the average potential (after 20microbursts) measured in the monkey thalamus while a pulse burst havingmicrobursts of four pulses each was applied to the vagus nerve. Theinter-microburst interval was about 4 seconds and the interpulseinterval was about 3 milliseconds.

FIG. 3E provides nine exemplary traces of the potential measured insidea monkey's thalamus while various exogenous electrical signals wereapplied to the vagus nerve of the monkey. Each of the traces illustratesthe average potential (after 20 microbursts) measured in the monkeythalamus while the exogenous electrical signals was applied to themonkey's vagus nerve. Each of the exogenous electrical signals includeda series of microbursts having a selected number of pulses each. Thepulses of the microbursts of the exogenous electrical signals of thetopmost row have an interpulse interval of 3 milliseconds. The pulses ofthe microbursts of the exogenous electrical signals of the middle rowhave an interpulse interval of 6 milliseconds. The pulses of themicrobursts of the exogenous electrical signals of the bottom row havean interpulse interval of 9 milliseconds.

FIG. 3F provides three exemplary traces of the potential measured insidea monkey's thalamus while various exogenous electrical signals wereapplied to the vagus nerve of the monkey. Each of the traces illustratesthe average potential (after 20 microbursts) measured in the monkeythalamus while the exogenous electrical signals was applied to themonkey's vagus nerve. All of the exogenous electrical signals included aseries of microbursts having three pulses each. The pulses had aninterpulse interval of 9 milliseconds. The exogenous electrical signalused to generate the leftmost trace included microbursts separated by aninter-microburst interval of about 6 seconds. The exogenous electricalsignal used to generate the middle trace included microbursts separatedby an inter-microburst interval of about 2 seconds. The exogenouselectrical signal used to generate the rightmost trace includedmicrobursts separated by an inter-microburst interval of about 0.5seconds.

FIG. 4A provides four exemplary traces of the potential measured insidea monkey's thalamus while various exogenous electrical signals wereapplied to the vagus nerve of the monkey. For all of the exogenouselectrical signals, the inter-microburst interval was about 4 secondsand the interpulse interval was about 3 milliseconds.

A topmost trace illustrates the average potential (after 20 pulses)measured in the monkey thalamus while a pulse burst having a series ofuniformly spaced apart pulses was applied to the monkey's vagus nerve.The spacing between the pulses was about 4 seconds.

A second trace from the top depicts the average potential (after 20microbursts) measured in the monkey thalamus while a pulse burst havingmicrobursts of two pulses each was applied to the vagus nerve.

A third trace from the top depicts the average potential (after 20microbursts) measured in the monkey thalamus while a pulse burst havingmicrobursts of three pulses each was applied to the vagus nerve.

The bottommost trace depicts the average potential (after 20microbursts) measured in the monkey thalamus while a pulse burst havingmicrobursts of four pulses each was applied to the vagus nerve.

FIG. 4B provides five exemplary traces of the potential measured insidea monkey's thalamus while various exogenous electrical signals includingmicrobursts having two pulses each, the microbursts being separated byan inter-microburst interval of about 4 seconds, were applied to thevagus nerve of the monkey. Each of the traces illustrates the averagepotential (after 20 microbursts) measured in the monkey thalamus whilethe exogenous electrical signals was applied to the monkey's vagusnerve.

The interpulse interval between the pulses of the microbursts of theexogenous electrical signal was about 40 milliseconds in the topmosttrace.

The interpulse interval between the pulses of the microbursts of theexogenous electrical signal was about 20 milliseconds in the tracesecond from the top.

The interpulse interval between the pulses of the microbursts of theexogenous electrical signal was about 10 milliseconds in the trace thirdfrom the top.

The interpulse interval between the pulses of the microbursts of theexogenous electrical signal was about 6.7 milliseconds in the tracefourth from the top.

The interpulse interval between the pulses of the microbursts of theexogenous electrical signal was about 3 milliseconds in the bottommosttrace.

FIG. 4C provides five exemplary traces of the potential measured insidea monkey's thalamus while various exogenous electrical signals includingmicrobursts having two pulses each, the pulses of each of themicrobursts being separated by an interpulse interval of about 6.7seconds, were applied to the vagus nerve of the monkey. Each of thetraces illustrates the average potential (after 20 microbursts) measuredin the monkey thalamus while the exogenous electrical signals wasapplied to the monkey's vagus nerve.

The inter-microburst interval between the microbursts of the exogenouselectrical signal used in the topmost trace corresponded to themicrobursts occurring at a microburst frequency of about 10 Hz.

The inter-microburst interval between the microbursts of the exogenouselectrical signal used in the trace second from the top corresponded tothe microbursts occurring at a microburst frequency of about 3 Hz.

The inter-microburst interval between the microbursts of the exogenouselectrical signal used in the trace third from the top corresponded tothe microbursts occurring at a microburst frequency of about 1 Hz.

The inter-microburst interval between the microbursts of the exogenouselectrical signal used in the trace fourth from the top corresponded tothe microbursts occurring at a microburst frequency of about 0.3 Hz.

The inter-microburst interval between the microbursts of the exogenouselectrical signal used in the bottommost trace corresponded to themicrobursts occurring at a microburst frequency of about 0.25 Hz.

FIG. 5 illustrates a system for using a conventional EEG device tooptimize an exogenous electrical signal used for VNS stimulationaccording to the present disclosure.

FIG. 6 provides an exemplary EEG illustrating the vagal evoked potentialelicited by an exogenous electrical signal constructed according to thepresent invention.

FIG. 7 illustrates an exemplary embodiment of an electrical signalgenerator programming and/or reprogramming device for use with theelectrical signal generator of FIG. 2A-2B.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides novel techniques, alone or incombination, to improve the efficacy of VNS used in the treatment of avariety of medical conditions, including disorders of the nervoussystem, such as epilepsy and depression. The following disclosuredescribes various embodiments of a novel method and its associatedapparatus for improving VNS therapies. According to the presentdisclosure, these novel techniques are particularly useful for treatingepilepsy and depression. However, it is envisioned that these same noveltechniques may be used to treat a variety of disorders and conditionsthat include a physiological relationship to the nervous system, such asneuropsychiatric disorders, eating disorders/obesity, traumatic braininjury/coma, addiction disorders, dementia, sleep disorders, pain,migraine, endocrine/pancreatic disorders (including but not limited todiabetes), motility disorders, hypertension, congestive heartfailure/cardiac capillary growth, hearing disorders, angina, syncope,vocal cord disorders, thyroid disorders, pulmonary disorders, andreproductive endocrine disorders (including infertility). Thus, based onthe aforementioned relationship to the nervous system, these disordersand conditions, including epilepsy and depression, are collectivelyreferred to herein as disorders of the nervous system, even if notconventionally described as such.

One of the novel techniques includes synchronizing portions of anexogenous electrical signal with the endogenous afferent activity of thevagus nerve, primarily the endogenous afferent activity originating fromreceptors in the heart and lungs. Stimulating the vagus nerve insynchrony with endogenous vagal rhythms, in particular with cardiaccycle and heart rate variability (HRV), enhances therapeutic efficacy ofVNS.

In the prior art, the exogenous electrical signal applied to the vagusnerve during conventional VNS is often referred to as a pulse burst. Thepulse burst typically includes a series of uniformly spaced apartsubstantially identical pulses, i.e., a simple pulse train. The VNSapplied to treat disorders of the nervous system may include multiplepulse bursts separated by an interburst delay.

An individual pulse burst may be triggered automatically or manually. Inmany prior art devices, a pulse burst may be triggered by the detectionof a medical event such as a seizure, or may be triggered manually bythe user or a medical professional. Alternatively, pulse bursts mayoccur at regular intervals separated by a predetermined interburstdelay. Typically, the interburst delay is about five minutes, 30minutes, or 60 minutes.

The pulses of the conventional VNS pulse bursts are appliedasynchronously, i.e., asynchronous with both the cardiac and lungcycles. As mentioned above, conventional VNS is generally applied every5 minutes in a 7 second to one minute pulse burst (see FIG. 3A for aportion of an exemplary burst) of uniformly spaced apart pulses havingan pulse current amplitude of about 0.5 mA to about 2.0 mA. The pulsesare delivered at about 20 Hz to about 50 Hz. Each of the pulses may havea width of about 0.5 milliseconds. While monophasic pulses are generallyused, biphasic pulses may also be used. As used herein, the term“pulses” refers to both monophasic and biphasic pulses.

In the present invention, the pulses within a pulse burst are patternedor otherwise organized to improve and/or optimize stimulation of thevagus nerve and/or structures of the brain in communication therewith.The natural endogenous afferent activity in the left and right vagusnerves predominantly occurs immediately following each cardiaccontraction and during each inspiration. Further, the timing of theendogenous afferent activity in the left and right vagus nerves varieswith heart rate, breathing rate, and emotional state. However, becausethe left and right vagus nerves innervate different portions of theheart, the timing of the afferent activity in the left vagus nerve maydiffer from the timing of the afferent activity in the right vagusnerve. Consequently, the patterning of the pulse burst may be differentfor the right and left vagus nerves. As is appreciated by those ofordinary skill in the art, the pulse burst is generally applied to theleft vagus nerve because VNS stimulators implanted on the right sideapplying a pulse burst to the right vagus nerve are associated with anincrease in patient mortality. As used herein, the term “vagus nerve”may refer to either the left or right vagus nerve.

According to one aspect of the present invention, a novel exogenouselectrical signal is applied to the vagus nerve. The novel exogenouselectrical signal is configured to augment the natural endogenousafferent activity in the vagus nerve by timing the pulses within a pulseburst in an improved and more effective manner. In particularembodiments, as will be described in detail below, the pulses within thepulse burst may be organized into sub-bursts or microbursts (each havingabout 2 to about 20 pulses) that are synchronized with the endogenousafferent activity in the vagus nerve to augment the endogenous afferentactivity therein.

Referring to FIG. 1, a trace 100 of a portion of an exemplary embodimentof the novel exogenous electrical signal is provided. Located above thetrace 100 in FIG. 1, an exemplary electrocardiogram (ECG) trace 120depicting cardiac activity detected by an electrocardiograph (not shown)is provided. The novel exogenous electrical signal includes a pulseburst 130 organized into a series of microbursts 170. Each of themicrobursts 170 is synchronized with a portion of the cardiac cycledepicted in the ECG trace 120. In particular, each of the microbursts170 is synchronized with the QRS wave portion 174 of the ECG trace 120,so that endogenous cardiac-related and respiration-related vagalafferent activity is augmented by the microbursts 170 of the exogenouselectrical signal.

As illustrated in FIG. 1, each of the microbursts 170 may be triggeredby an R-wave portion 176 of the QRS wave portion 174. Without beingbound by theory, it is believed that synchronizing the application ofthe microbursts 170 of the exogenous electrical signal to the vagusnerve with the detection of the R-wave portion 176 of the patient'scardiac cycle may increase the efficacy of VNS therapy by entraining theexogenous electrical signal with the endogenous cyclic facilitation ofcentral vagal afferent pathways. Each of the microbursts 170 beginsafter the elapse of a delay period, which comprises a variable timeperiod that may range, e.g., from about 10 milliseconds to about 1000milliseconds following detection of the R-wave portion 176. In variousembodiments, the delay period may be less than about 10 milliseconds.Further, in some embodiments, the delay period may be about 10milliseconds to about 500 milliseconds or about 10 milliseconds to about800 milliseconds. In further embodiments, the delay period is less than1000 milliseconds. In other embodiments, the delay period may beomitted. Each of the delay periods may comprise a predetermined durationsuch as about 10 milliseconds, or may comprise a random time durationwithin a predetermined minimum and maximum time duration, e.g., a randomtime duration from about 10 milliseconds to about 1000 milliseconds.Further, as will be described below, the duration of the delay periodpreceding each microburst 170 may be determined empirically.

For example, the leftmost (first) microburst 170 begins after a delayperiod “D1,” the next (or second) microburst 170 begins after a delayperiod “D2,” and the third microburst 170 begins after a delay period“D3.” The delay period “D1” may be shorter than the delay periods “D2”and “D3.” Additionally, the delay period “D2” may be shorter than thedelay period “D3.” In alternate embodiments, the delay periods “D1,”“D2,” and “D3” may be substantially identical. In further embodiments,the delay period “D1,” may be larger than delay period “D2,” which maybe larger than delay period “D3.” Embodiments wherein each of the delayperiods “D1,” “D2,” and “D3” is selected randomly within a specifiedrange of delay values or determined empirically are also within thescope of the present invention. As will be appreciated by those of skillin the art, still further embodiments of the present invention mayinclude a variety of delay period combinations that can be identifiedand implemented by routine experimentation. Each of these is consideredto be within the scope of the present invention. While three delayperiods have been described with respect to FIG. 1, it is apparent tothose of ordinary skill that a delay period may precede each microburstof a pulse burst and the duration of the delay period may be determinedempirically or randomly.

In various embodiments, the synchronization of the exogenous electricalsignal further comprises not providing pulses during selected portionsof the cardiac cycle, such as periods in the opposite half of thecardiac and respiratory duty cycles, when the central pathways areinhibited. Again without being bound by theory, it is believed thatpulses applied to the vagus nerve during the opposite half of thecardiac and respiratory duty cycles are less effective becauseendogenous signals in this part of the cardiac and/or respiratory cyclesare less significant, in terms of their information content, formodulating those portions of the brain relevant to homeostasismechanisms implicated in medical conditions such as epilepsy anddepression. Thus, at least a portion of the asynchronous exogenouselectrical signal delivered by current stimulation algorithms, such asconventional VNS, may be therapeutically irrelevant.

Because the exogenous electrical signal is typically delivered by animplanted device powered by a battery, the delivery of irrelevantsignals may result in unnecessary battery depletion. Further, the pulseburst sometimes causes the patient's vocal cords to contract causinghis/her voice to become horse, which is uncomfortable and makes talkingdifficult. Sometimes, the pulse burst causes neck pain and may causecardiac problems. Therefore, reducing the number of pulses maycontribute to patient comfort and/or safety.

Synchronizing the microbursts 170 of the exogenous electrical signalwith each individual QRS wave portion 174 also tracks the naturalvariability in vagal afferent activity that occurs during breathing andemotional shifts. This heart rate variability (HRV) is a function ofrespiration and efferent sympathovagal tone. During inspiration, theheart rate accelerates and during expiration it decelerates. Thus, anR-R interval (i.e., the time that elapses between successive R waveportions 176) appearing in the ECG is shorter during inspiration andlonger during expiration, producing HRV. HRV is also known asrespiratory sinus arrhythmia. Additionally, it is well established thata larger HRV is associated with greater physical health, includinggreater immune function, lower risk of cardiac arrhythmia, and bettermood, than a smaller HRV.

HRV is greatly increased during meditation, and HRV is increased easilyby slow, paced breathing. Synchronizing the microbursts 170 of theexogenous electrical signal with each QRS wave portion 174 of thecardiac cycle utilizes and accentuates the positive association of HRVwith overall bodily health. Further, it helps ensure that themicrobursts 170 of the exogenous electrical signal are synchronized withvariances in the cardiac cycle. Consequently, it may be beneficial forthe patient to begin paced breathing during the pulse burst. Further, itmay improve the efficacy of the exogenous electrical signal if the pulseburst is triggered while the patient is performing paced breathing.

Referring to FIG. 2A-2B, a suitable electrical signal generator 200,such as a VNS stimulator, known in the art has one or more electrodes220A and 220B coupled to the vagus nerve for delivering electricalpulses thereto. In embodiments wherein the microbursts of the exogenouselectrical signal are synchronized with the cardiac cycle, optionally,the electrical signal generator 200 has the capacity to detect cardiacsignals and produce an ECG trace for the purpose of avoiding thedeliverance of conventional VNS in the event of cardiac arrest. In otherwords, the suitable electrical signal generator 200 for use with thepresent invention may include one or more sensors, such as sensingelectrodes 210A and 210B positioned to detect cardiac electricalsignals, and the onboard capability of analyzing those signals. Inparticular, the electrical signal generator 200 may be capable ofidentifying the R wave portion of the cardiac signal. In alternativeembodiments, the sensor(s) may include an acoustic device configured todetect the cardiac cycle.

In embodiments wherein the microbursts of the exogenous electricalsignal are synchronized with the cardiac cycle, the electrical signalgenerator 200 may be modified or programmed to deliver the novelexogenous electrical signal. The modifications include replacing a morecommon open-loop or non-feedback stimulation system with a feedbacksystem utilizing one or more sensing electrodes 210A and 210B to detectthe QRS wave portion 174 of the ECG trace 120 (see FIG. 1). Themodification of the electrical signal generator 200 is effected byprogramming the electrical signal generator 200 to initiate a microburst170 after the elapse of the delay period, such as delay period “D1”,delay period “D2”, or delay period “D3,” following the detection of theQRS wave portion 174. Again, while three exemplary delay periods havebeen described, a delay period may precede each microburst and suchembodiments are within the scope of the present invention. Further,embodiments in which no delay period precedes a microburst are alsowithin scope of the present invention. As is apparent to those ofordinary skill in the art, embodiments of the electrical signalgenerator 200 that have the feedback system for detecting the QRS waveportion 174 without modification are also within the scope of thepresent invention.

FIG. 2B is a block diagram of various components of the electricalsignal generator 200. The electrical signal generator 200 may include aprogrammable central processing unit (CPU) 230 which may be implementedby any known technology, such as a microprocessor, microcontroller,application-specific integrated circuit (ASIC), digital signal processor(DSP), or the like. The CPU 230 may be integrated into an electricalcircuit, such as a conventional circuit board, that supplies power tothe CPU 230. The CPU 230 may include internal memory or memory 240 maybe coupled thereto. The memory 240 is a computer readable medium thatincludes instructions or computer executable components that areexecuted by the CPU 230. The memory 240 may be coupled to the CPU 230 byan internal bus 250.

The memory 240 may comprise random access memory (RAM) and read-onlymemory (ROM). The memory 240 contains instructions and data that controlthe operation of the CPU 230. The memory 240 may also include a basicinput/output system (BIOS), which contains the basic routines that helptransfer information between elements within the electrical signalgenerator 200. The present invention is not limited by the specifichardware component(s) used to implement the CPU 230 or memory 240components of the electrical signal generator 200.

The electrical signal generator 200 may also include an external deviceinterface 260 permitting the user or a medical professional to entercontrol commands, such as a command triggering the delivery of the novelexogenous electrical signal, commands providing new instructions to beexecuted by the CPU 230, commands changing parameters related to thenovel exogenous electrical signal delivered by the electrical signalgenerator 200, and the like, into the electrical signal generator 200.The external device interface 260 may include a wireless user inputdevice. The external device interface 260 may include an antenna (notshown) for receiving a command signal, such as a radio frequency (RF)signal, from a wireless user input device such as a computer-controlledprogramming wand 800 (see FIG. 7). The electrical signal generator 200may also include software components for interpreting the command signaland executing control commands included in the command signal. Thesesoftware components may be stored in the memory 240.

The electrical signal generator 200 includes a cardiac signal interface212 coupled to sensing electrodes 210A and 210B for receiving cardiacelectrical signals. The cardiac signal interface 212 may include anystandard electrical interface known in the art for connecting a signalcarrying wire to a conventional circuit board as well as any componentscapable of communicating a low voltage time varying signal received fromthe sensing electrodes 210A and 210B through an internal bus 214 to theCPU 230. The cardiac signal interface 212 may include hardwarecomponents such as memory as well as standard signal processingcomponents such as an analog to digital converter, amplifiers, filters,and the like.

The electrical signal generator 200 includes an exogenous electricalsignal interface 222 coupled to electrodes 220A and 220B for deliveringthe exogenous electrical signal to the vagus nerve. The exogenouselectrical signal interface 222 may include any standard electricalinterface known in the art for connecting a signal carrying wire to aconventional circuit board as well as any components capable ofcommunicating a low voltage time varying signal generated by the CPU 230or a signal generating device controlled by the CPU 230 to theelectrodes 220A and 220B through an internal bus 252. The exogenouselectrical signal interface 222 may include hardware components such asmemory as well as standard signal processing components such as adigital to analog converter, amplifiers, filters, and the like.

The various components of the electrical signal generator 200 may becoupled together by the internal buses 214, 250, 252, and 254. Each ofthe internal buses 214, 250, 252, and 254 may be constructed using adata bus, control bus, power bus, I/O bus, and the like.

The electrical signal generator 200 may include instructions 280executable by the CPU 230 for processing and/or analyzing the cardiacelectrical signals received by the sensing electrodes 210A and 210B.Additionally, the electrical signal generator 200 may includeinstructions 280 executable by the CPU 230 for generating an exogenouselectrical signal delivered to the vagus nerve by the electrodes 220Aand 220B. These instructions may include computer readable softwarecomponents or modules stored in the memory 240. The instructions 280 mayinclude a Cardiac Signal Monitoring Module 282 that generates atraditional ECG trace from the cardiac electrical signals. The CardiacSignal Monitoring Module 282 may record the ECG trace in the memory 240.

As is appreciated by those of ordinary skill in the art, generating anECG trace from an analog cardiac electrical signal may require digitalor analog hardware components, such as an analog to digital converter,amplifiers, filters, and the like and such embodiments are within thescope of the present invention. In one embodiment, some or all of thesecomponents may be included in the cardiac signal interface 212. In analternate embodiment, some or all of these components may be implementedby software instructions included in the Cardiac Signal MonitoringModule 282. The Cardiac Signal Monitoring Module 282 may include anymethod known in the art for generating an ECG trace from a time varyingvoltage signal.

As mentioned above, the unmodified electrical signal generator 200monitors cardiac electrical signals for the purposes of detecting acardiac arrest. The Cardiac Signal Monitoring Module 282 may be modifiedto include instructions for detecting or identifying the R wave portionof the ECG trace. The R wave portion of the ECG trace may be detectedusing any method known in the art. While the electrical signal generator200 has been described as having the Cardiac Signal Monitoring Module282, embodiments in which the functionality of the Cardiac SignalMonitoring Module 282 is performed by more than one software componentare within the scope of the present invention.

The unmodified electrical signal generator 200 generates the exogenouselectrical signal used by conventional VNS. The instructions 280 includea Signal Generation Module 284 for instructing the CPU 230 how and whento generate the conventional VNS exogenous electrical signal and deliverit to the vagus nerve via the electrodes 220A and 220B. The SignalGeneration Module 284 may be modified to generate the inventive novelexogenous electrical signal. Specifically, the Signal Generation Module284 may be modified to include instructions directing the CPU 230 tosynchronize the microbursts of the exogenous electrical signal with theR wave portion of the ECG trace. The Signal Generation Module 284 maydetermine the values of the various parameters used to define the novelexogenous electrical signal based on simulating the endogenous afferentactivity of the vagus nerve as described herein. Alternatively, thevalues of the various parameters may be stored in the memory 240 andused by the Signal Generation Module 284 to generate the novel exogenouselectrical signal. The various parameters may be entered into the memory240 by the external device interface 260 which permits the user ormedical professional to enter control commands, including commandschanging parameters related to the novel exogenous electrical signaldelivered by the electrical signal generator 200, and the like, into theelectrical signal generator 200.

While the electrical signal generator 200 has been described as havingthe Signal Generation Module 284, embodiments in which the functionalityof the Signal Generation Module 284 is performed by more than onesoftware component are within the scope of the present invention.

Examples of suitable electrical signal generators for use with thepresent invention include a model 103 VNS stimulator (formally referredto as the Gen39) produced by Cyberonics, Inc. (Houston, Tex.), model 104VNS stimulator also produced by Cyberonics, Inc., and the like. Theanalog recording and ECG recognition capacity of these VNS stimulatorsenable their onboard processor to be programmed to produce pulse burstsof vagal stimulation having the desired parameters at variable delayperiods following the detection of the R-wave of the ECG. The delayperiods may comprise a predetermined, programmable duration such asabout 10 milliseconds, or may comprise a random time duration within apredetermined programmable minimum and maximum time duration, e.g., arandom time duration from about 10 milliseconds to about 1000milliseconds. The predetermined, programmable duration(s) of the delayperiod(s) may be determined empirically using methods described below.

While a relatively sophisticated embodiment of the electrical signalgenerator 200 is described above, those of ordinary skill appreciatethat simpler devices, such as a device configured to deliver theexogenous electrical signal asynchronously (i.e., an exogenouselectrical signal having microbursts that are not synchronized with thecardiac cycle) are also within the scope of the present invention. Theelectrical signal generator 200 may provide an asynchronous exogenouselectrical signal having microbursts spaced at regular or variableintervals. For example, the microbursts may occur at least every 100milliseconds or at the microburst frequency of about 0.25 Hz to about 10Hz. The pulses within the microbursts may be spaced at regular orvariable intervals. Further, less sophisticated embodiments of theelectrical signal generator 200 include electrical signal generatorsthat are pre-programmed with the exogenous electrical signal parameters(e.g., pulse width, pulse frequency, interpulse interval(s), microburstfrequency, number of pulses in the microbursts, etc.) beforeimplementation and may retain those pre-programmed parameter valuesthroughout the functional life of the electrical signal generator.Alternatively, electrical signal generators configured to generate anasynchronous exogenous electrical signal may be programmable afterimplementation. For example, the computer-controlled programming wand800 (see FIG. 7) may be used in the manner described above to programsuch electrical signal generators. As is readily apparent to those ofordinary skill, the present invention is not limited by the particularelectrical signal generator used to generate the inventive exogenouselectrical signal.

In one aspect, the microbursts of the exogenous electrical signal may bedelivered following every detected R-wave occurring within apredetermined pulse burst period, i.e., the period of time during whichthe exogenous electrical signal is generated. In another embodiment, themicrobursts may be applied to the vagus nerve only during theinspiratory phase. This may be implemented by programming the electricalsignal generator 200 to apply a microburst only on the shortening R-Rintervals during HRV, i.e., only on an R-wave having an R-R intervalless than the preceding R-R interval, or less than a moving average forseveral R-R intervals, e.g., less than a 5 or 10 R-R interval movingaverage. In further embodiments, the electrical signal generator 200 mayinclude a sensor, such as a strain gauge or acoustic device, thatdetects various biometric parameters such as heartbeat and therespiratory cycle. For example, a strain gauge may be used to determineinspiration is occurring by identifying when the chest is expanding. Theinvention is not limited by the method used to determine inspiration isoccurring, the R-R interval, and/or whether the R-R intervals areshortening for the purposes of determining inspiration is occurring.

The timing parameters defining how the microbursts of the exogenouselectrical signal are synchronized with the cardiac cycle for maximaltherapeutic efficacy may be determined empirically, and according toparticular embodiments, are individually optimized for each patient (asdescribed below). In alternate embodiments, patients may perform pacedbreathing, e.g., taking a breath at a frequency of about 0.1 Hz, duringperiods when the exogenous electrical signal is being delivered to thevagus nerve, to facilitate or increase the amount of HRV.

In further embodiments, the various parameters of the cardiac cyclesynchronized exogenous electrical signal may be varied, includingwithout limitation the duration of the pulse burst, the delay period(s)following R-wave detection, the number of pulses comprising amicroburst, the interpulse interval (i.e., the amount of time separatingone pulse from an adjacent pulse), and the inter-microburst interval(i.e., the amount of time between successive microbursts). Further,these parameters may be selectively associated with particular R-wavesof the respiratory cycle, depending on the length of each precedingR-R-interval. In various embodiments, these parameters are empiricallyoptimized for each patient.

In another aspect of the present invention, a method of providing anexogenous electrical signal capable of inducing a much larger vagalevoked potential (VEP) than that induced by conventional VNS isprovided. The exogenous electrical signal provided to the vagus nervecomprises a pulse burst including a series of microbursts. As describedabove the inter-microburst interval may be determined by the cardiaccycle.

An example of a portion of a pulse burst 300 used in conventional VNSmay be viewed in FIG. 3A. The pulse burst 300 includes a plurality ofuniformly spaced apart pulses 302 occurring about every 20 millisecondsto about every 50 milliseconds, i.e., occurring at a frequency of about20 Hz to about 50 Hz. A conventional pulse burst, such as pulse burst300 may have a pulse burst duration of about 7 seconds to about 60seconds (resulting in a pulse burst having from about 140 to about 3000pulses or more). Each pulse 302 may have a width or duration of about 50microseconds to about 1000 microseconds (μsec) and a pulse current ofabout 0.1 mA to about 8 mA.

The pulse burst 300 may be separated from a pulse burst identical topulse burst 300 by an interburst interval of about 5 min. Sometimes, aninterburst interval of about 30 min. or about 60 min. is used. Infurther implementations, the pulse burst 300 is triggered by the onsetof a medical event, such as a seizure, or is triggered by the user or amedical professional. In such embodiments, the interburst intervalvaries.

FIG. 3B provides a trace 304 of the potential measured in the monkeythalamus while the conventional pulse burst 300 (see FIG. 3A) ofuniformly spaced pulses 302 having an interpulse interval of 4 secondswas applied to the vagus nerve. The trace 304 shows the potential insidethe thalamus immediately after each of the pulses 302 is delivered tothe vagus nerve. An increased VEP 305 occurs after the first pulse 302.However, as illustrated by FIG. 3B, little to no increased VEP isobserved after the successive pulses 302 in the series. The averagepotential inside the thalamus observed over 20 pulses is provided by atopmost trace 320 in FIG. 4A. The VEP is the difference between aminimum average potential in the trace 320 observed after an averagedpulse portion 303 of the trace 320 and a maximum average potential inthe trace 320 observed after the averaged pulse portion 303 of the trace320. However, as illustrated in the trace 320, the minimum and themaximum potentials are not clearly identifiable.

Referring to FIG. 3C, a portion of a pulse burst 400 of the exogenouselectrical signal constructed in accordance with the present inventionis provided. As is apparent to those of ordinary skill, unlike theuniformly spaced pulses 302 of the pulse burst 300, the pulses 402 and404 of the pulse burst 400 are patterned or structured within the pulseburst 400. Specifically, the pulses 402 and 404 are arranged intomicrobursts 410A, 410B, and 410C. In the embodiment depicted in FIG. 3C,each of the microbursts 410A, 410B, and 410C includes the pulse 402followed by the pulse 404. Each of the individual pulses 402 and 404 inthe pulse burst 400 resemble the pulses 302 of the conventional VNSpulse burst 300 and have a pulse width of about 50 microseconds to about1000 microseconds (μsec) and a pulse current of about 0.25 mA to about 8mA. In particular embodiments, the pulse current is less than about 2mA.

While the individual pulses 402 and 404 in the pulse burst 400 resemblethe pulses 302 of the conventional VNS pulse burst 300 (i.e., each has apulse width of about 50 microseconds to about 1000 microseconds (μsec)and a pulse current of about 0.25 mA to about 8 mA) the number of pulses402 and 404 in the pulse burst 400 is markedly smaller than the numberof pulses 302 in the pulse burst 300, assuming the pulse burst 400 hasthe same duration as the pulse burst 300. As mentioned above, theconventional pulse burst 300 may have a pulse burst duration of about 7seconds to about 60 seconds and a pulse frequency of about 20 Hz toabout 50 Hz, resulting in a pulse burst having from about 140 to about3000 pulses or more. If the pulse burst 400 has a duration of about 7seconds to about 60 seconds, and the microbursts are delivered every 0.5seconds, roughly corresponding to the interval between heart beatsduring inspiration, the pulse burst 400 will have about 30 pulses toabout 242 pulses.

As mentioned above, reducing the number of pulses delivered to the vagusnerve may help prolong battery life as well as improve patient comfortand safety. Further, patterning the pulses of the pulse burst 400 intomicrobursts, such as microbursts 410A, 410B, and 410C increases the VEPobserved in the brain. Because the VEP is increased, the currentamplitude may be reduced, further increasing patient comfort and/orsafety. The increased VEP may also improve the therapeutic effects ofthe exogenous electrical signal.

Referring to FIG. 3D, a trace 306 illustrating the average potentialinside the monkey thalamus observed over a series of 20 microbursts,each having a series of four pulses with a 3 milliseconds interpulseinterval separating the pulses, is provided. The microbursts of FIG. 3Dare separated by a 4 second inter-microburst interval. The VEP is thedifference between a minimum 307 in the trace 306 observed after anaveraged microburst portion 309 of the trace 306 and a maximum 308 inthe trace 306 observed after the averaged microburst portion 309 of thetrace 306. The difference between the minimum 307 and the maximum 308 ofthe trace 306 is clearly larger than the difference between theunidentifiable minimum and the unidentifiable maximum of the trace 320(see FIG. 4A and the pulse intervals after the third pulse in FIG. 3B).Therefore, without changing any parameters other than the number ofpulses delivered every 4 sec., i.e., delivering a microburst instead ofa single pulse, the VEP potential can be increased or enhanced.

The pulses 402 and 404 within the first microburst 410A are separated byan interpulse interval “P1A.” The pulses 402 and 404 within the secondmicroburst 410B are separated by an interpulse interval “P1B.” Thepulses 402 and 404 within the third microburst 410C are separated by aninterpulse interval “P1C.” In most cases, the interpulse intervals“P1A,” “P1B,” and “P1C” separating the pulses 402 and 404 are shorterthan the interpulse intervals between the pulses 302 used inconventional VNS therapy. The first interpulse interval “P1A” may rangefrom about one millisecond to about 50 milliseconds. Typically, thefirst interpulse interval “P1A” may range from about 2 milliseconds toabout 10 milliseconds. In some embodiments, Typically, the firstinterpulse interval “P1A” may range from about 3 milliseconds to about10 milliseconds. In various embodiments, the interpulse interval “P1B”may be substantially equal to the interpulse interval “P1A.” Subsequentinterpulse intervals occurring after the interpulse interval “P1B,” suchas interpulse interval “P1C,” may be substantially equal to theinterpulse interval “P1B.” In alternate embodiments, the interpulseinterval “P1A” may be larger than the interpulse interval “P1B,” whichmay be larger than the interpulse interval “P1C.” In furtherembodiments, the interpulse interval “P1A” may be smaller than theinterpulse interval “P1B,” which may be smaller than the interpulseinterval “P1C.” In various embodiments, the interpulse intervals “P1A,”“P1B,” and “P1C” may be selected randomly from a predetermined range ofinterpulse interval values. In further embodiments, the interpulseintervals may be variable and determined empirically, as describedbelow.

The first microburst 410A is separated from the microburst 410B by aninter-microburst interval “P2.” Each microburst may be considered anevent occurring at a microburst frequency (i.e., the inverse of the sumof the inter-microburst interval “P2” and the duration of themicroburst). The microburst frequency may range from about 0.25 Hz toabout 10 Hz. It may be beneficial to use a microburst frequency thatapproximates the R-R cycle of the patient.

In various embodiments, the pulses within a microburst may be patternedor structured. For example, referring to FIG. 1, the portion of thepulse burst 130 is provided. The pulse burst 130 includes fivemicrobursts 170, each triggered by the R-wave portion 176 of the cardiaccycle depicted in the ECG trace 120. Each microburst 170 includes fourpulses 182, 184, 186, and 188. The first pulse 182 begins after thepredetermined delay time “D1” has elapsed following the identificationof the R-wave portion 176. The pulse 184 follows the pulse 182 after afirst interpulse delay has elapsed. Then, after a second interpulseinterval, the pulse 186 is generated. Finally, after a third interpulseinterval, the pulse 188 is generated. In the embodiment depicted in FIG.1, the interpulse intervals increase in duration along the series ofpulses. However, the interpulse intervals may be determined empiricallyand individualized for each patient. While each microburst 170 in FIG. 1has only four pulses, microbursts 170 having 2 to 20 pulses, andconsequently 1 to 19 interpulse intervals, are within the scope of thepresent invention. In some embodiments, the microbursts 170 may have 2to 15 pulse, or alternatively, 3 to 6 pulses.

In various embodiments, the pulse burst 400 may be separated from apulse burst identical to pulse burst 400 or a dissimilar pulse burst byan interburst interval of about 5 minutes to about 240 minutes.Alternatively, the interburst interval may be about 200 milliseconds toabout 24 hours. In further embodiments, the pulse burst is appliedcontinuously. The pulse burst may have a duration of about 100milliseconds to about 60 minutes. In various embodiments, the pulseburst duration is determined empirically for a particular patient and/ormedical condition. In further embodiments, the pulse burst 400 istriggered by the onset of a medical event, such as a seizure, or istriggered by the user or a medical professional. In such embodiments,the interburst interval varies. Optionally, the pulse burst 400 may beterminated automatically by the onset of a medical event, such ascardiac arrest, or manually the user or a medical professional. In suchembodiments, the pulse burst duration varies.

Pulses, such as pulses 182, 184, 186, and 188, arranged intomicrobursts, such as microburst 170, are capable of evoking an enhancedvagal evoked potential (eVEP) in the patient's brain that issignificantly greater than an VEP evoked by conventional VNS (see FIG.3A). However, this eVEP may attenuate as the number of pulses within amicroburst increases beyond an optimal number of pulses. Framed a littledifferently, the eVEP attenuates as the microburst duration increasesbeyond an optimal duration. Thus, for example, where a microburstexceeds 2 pulses to 5 pulses, the eVEP begins to diminish, and if morethan 20 pulses are provided, the eVEP essentially disappears. This maybe observed in FIG. 3E.

Referring to the top row of FIG. 3E, traces 370, 372, and 374 illustratethe average potential inside the monkey thalamus averaged over a seriesof 20 microbursts, each having a series of pulses separated by aninterpulse interval of 3 milliseconds. The microbursts of FIG. 3E areseparated by a 4 second inter-microburst interval. The number of pulseswithin the microbursts increase from left to right. In the leftmosttrace 370, the microbursts had 2 pulses each. In the center trace 372,the microbursts had 5 pulses each. And, in the rightmost trace 374, themicrobursts had 9 pulses each. Again, the VEP observed in each trace, isthe difference between a minimum in the trace observed after an averagedmicroburst portion (appearing at the left of the trace) and a maximum inthe trace observed after the averaged microburst portion of the trace.The top row clearly illustrates that using these parameters, microburstshaving 5 pulses produce a larger VEP than microbursts having 2 pulses.However, microbursts having 9 pulses produce a smaller VEP thanmicrobursts having 5 pulses.

Referring to the middle row of FIG. 3E, traces 380, 382, and 384illustrate the average potential inside the monkey thalamus averagedover a series of 20 microbursts, each having a series of pulsesseparated by an interpulse interval of 6 milliseconds. In the leftmosttrace 380, the microbursts had 2 pulses each. In the center trace 382,the microbursts had 3 pulses each. And, in the rightmost trace 384, themicrobursts had 6 pulses each. The middle row clearly illustrates thatusing these parameters, microbursts having 3 pulses produce a larger VEPthan microbursts having 2 pulses. However, microbursts having 6 pulsesproduce a smaller VEP than microbursts having 3 pulses.

Referring to the bottom row of FIG. 3E, traces 390, 392, and 394illustrate the average potential inside the monkey thalamus averagedover a series of 20 microbursts, each having a series of pulsesseparated by an interpulse interval of 9 milliseconds. In the leftmosttrace 390, the microbursts had 2 pulses each. In the center trace 392,the microbursts had 3 pulses each. And, in the rightmost trace 394, themicrobursts had 5 pulses each. The bottom row clearly illustrates thatusing these parameters, microbursts having 3 pulses produce a larger VEPthan microbursts having 2 pulses. However, microbursts having 5 pulsesproduce a smaller VEP than microbursts having 3 pulses.

Referring to the leftmost column of FIG. 3E, traces 370, 380, and 390illustrate the facilitation the first pulse provides to the second pulseof the microburst. The traces 372, 382, and 392 in the rightmost columnof FIG. 3E illustrate additional facilitation provided by addingadditional pulses to the microburst. However, the traces 374, 384, and394 in the rightmost column of FIG. 3E illustrate that if the durationof the microbursts is too long, the microburst extends into aninhibitory period of neural activity reducing the VEP observed in thethalamus of the monkey. Consequently, the VEP may be improved and/oroptimized by the selection of the number of pulses of the microbursts.

It may be helpful to define a microburst by its duration rather than thenumber of pulses. Experimental results related to optimizing microburstduration are illustrated in FIGS. 3E and 4B. For example, ignoring thepulse widths, FIG. 3E illustrates that the VEP begins to decline whenthe sum of the interpulse intervals within a single microburst exceedsabout 30 milliseconds. Consequently, for the monkey, the optimal sum ofthe interpulse intervals within a single microburst may be less than 30milliseconds and in some embodiments, less than 20 milliseconds. Thedata of FIG. 3E further indicates, a range of about 12 milliseconds toabout 18 milliseconds may be used. Human beings are larger and have aheart rate that is roughly half (about 180 beats/minute for the monkeyand about 70 beats/minute for a human). Therefore, one of ordinary skillwill recognize that by doubling the sum of the interpulse intervals, thesum of the interpulse intervals may be converted for use with a human.Based on this rough approximation, for humans, the optimal sum of theinterpulse intervals within a single microburst may be less than 80milliseconds and in some embodiments, the sum may be less than 60milliseconds. In further embodiments, the sum of the interpulseintervals within a single microburst may be less than about 40milliseconds and preferably about 12 milliseconds to about 40milliseconds. In some embodiments, the sum of the interpulse intervalswithin a single microburst may be about 10 milliseconds to about 80milliseconds. One of ordinary skill in the art will also recognizealternate methods of converting the sum of the interpulse intervalsdetermined in the experimental monkey data for use with a human and thatsuch embodiments are within the scope of the present invention. Further,the sum of the interpulse intervals for use with a human may bedetermined empirically using the empirical method described below.

Generally, the microburst duration (i.e., the sum of the interpulseintervals and the pulse widths within a microburst) may be less thanabout one second. In particular embodiments, the microburst duration maybe less than about 100 milliseconds. In particular embodiments,microbursts having a duration of about 4 milliseconds to about 40milliseconds may be used.

Referring to the top row of FIG. 3F, traces 391, 393, and 395 illustratethe average potential inside the monkey thalamus averaged over a seriesof 20 microbursts, each having a series of pulses separated by aninterpulse interval of about 9 milliseconds. The microbursts used tocreate the traces 391, 393, and 395 are separated by about a 6 second,about a 2 second, and about a 0.5 second inter-microburst interval,respectively. While the VEP in the trace 395 is less than the VEP in theother two traces 393, and 395, the trace 395 illustrates that the eVEPis present at the rate the QRS wave occurs in the cardiac cycle duringinspiration, i.e., about once every 0.5 second. Consequently,microbursts synchronized with the QRS wave during inspiration mayproduce eVEP in the thalamus and other brain structures in electricalcommunication therewith. Other parameters, such as interpulseinterval(s), delay period(s), pulse current amplitude, pulse width,pulse burst duration, and the like may be adjusted to improve and/oroptimize the VEP.

To maintain the eVEP, the present invention provides a microburst havingonly a small number of pulses as well as an inter-microburst intervalthat serves as a period during which the vagus nerve (and/or brainstructures in communication therewith) may recover from the microburst.Providing an appropriate inter-microburst interval helps ensure that thesucceeding microburst in the pulse burst of the exogenous electricalsignal is capable of generating the eVEP. In some embodiments, theinter-microburst interval is as long as or longer than the duration ofthe microburst. In another embodiment, the inter-microburst interval isat least 100 milliseconds. In further embodiments, the inter-microburstinterval may be as long as 4 seconds or 6 seconds. In some embodiments,the inter-microburst interval may be as long as 10 seconds. Eachmicroburst comprises a series of pulses that, in some embodiments, areintended to mimic the endogenous afferent activity on the vagus nerve.In one embodiment, the microburst may simulate the endogenous afferentvagal action, such as the action potentials associated with each cardiacand respiratory cycle.

The central vagal afferent pathways involve two or more synapses beforeproducing activity in the forebrain. Each synaptic transfer is apotential site of facilitation and a nonlinear temporal filter, forwhich the sequence of inter-microburst intervals and/or interpulseintervals within a microburst can be optimized. Without being bound bytheory, it is believed that the use of microbursts enhances VNS efficacyby augmenting synaptic facilitation and “tuning” the input stimulustrain to maximize the forebrain evoked potential.

FIG. 4A-4C illustrate the effects of modifying the various parameters ofthe exogenous electrical signal on the VEP measured in the thalamus of amonkey. FIG. 4A illustrates the effects of varying the number of pulsesin a microburst. FIG. 4B illustrates the effects of varying theinterpulse interval between the pulses of a microburst having only twopulses. FIG. 4C illustrates the effects of varying the inter-microburstinterval between adjacent microbursts having only two pulses each.

The topmost trace 320 of FIG. 4A provides the average potential (after20 pulses) measured in the monkey thalamus while a pulse burst ofuniformly spaced apart pulses having an interpulse interval of 4 secondswas applied to the vagus nerve.

A trace 340 of FIG. 4A depicts the average potential (after 20microbursts) measured in the monkey thalamus while a pulse burst havingmicrobursts of two pulses each was applied to the vagus nerve. Theinter-microburst interval was about 4 seconds and the interpulseinterval was about 3 milliseconds. The VEP (i.e., the difference betweenthe minimum and maximum potentials observed after each microburst) isnoticeably improved in the trace 340 when compared with the VEP of thetrace 320.

A trace 350 depicts the average potential (after 20 microbursts)measured in the monkey thalamus while a pulse burst having microburstsof three pulses each was applied to the vagus nerve. Theinter-microburst interval was about 4 seconds and the interpulseinterval was about 3 milliseconds. The VEP is noticeably improved in thetrace 350 when compared with the VEP of the trace 340.

A trace 360 depicts the average potential (after 20 microbursts)measured in the monkey thalamus while a pulse burst having microburstsof four pulses each was applied to the vagus nerve. The inter-microburstinterval was about 4 seconds and the interpulse interval was about 3milliseconds. The VEP is noticeably improved in the trace 360 whencompared with the VEP of the trace 350.

Referring to FIG. 4B, the effect of the interpulse interval on the VEPis illustrated. Traces 500, 510, 520, 530, and 540 depict the averagepotential (after 20 microbursts) measured in the monkey thalamus while apulse burst having microbursts of two pulses each, separated by aninter-microburst interval of 4 sec. was applied to the vagus nerve. Theinterpulse intervals were about 40 milliseconds, about 20 milliseconds,about 10 milliseconds, about 6.7 milliseconds, and about 3 millisecondsfor the traces 500, 510, 520, 530, and 540, respectively. The VEP isbarely visible in the trace 500. The VEP is noticeably improved in thetrace 510 when compared with the VEP of the trace 500. The VEP isnoticeably improved in the trace 520 when compared with the VEP of thetrace 510. The VEP is noticeably improved in the trace 530 when comparedwith the VEP of the trace 520. However, the VEP in the trace 540 isnoticeably less than the VEP 534 of the trace 530.

Referring to FIG. 4C, the effect of the inter-microburst interval on theVEP is illustrated. Traces 600, 610, 620, 630, and 640 depict theaverage potential (after 20 microbursts) measured in the monkey thalamuswhile a pulse burst having microbursts of two pulses each, the pulsesbeing separated by an interpulse interval of 6.7 milliseconds. wasapplied to the vagus nerve. The inter-microburst intervals correspondedto the microbursts occurring at a microburst frequency of about 10 Hz,about 3 Hz, about 1 Hz, about 0.3 Hz, and about 0.25 Hz for the traces600, 610, 620, 630, and 640, respectively. The VEP is barely visible inthe trace 600. Because the inter-microburst internal was sufficientlyshort, the trace 600 shows a second microburst artifact 606 to the rightof the first microburst artifact 602. The VEP is noticeably improved inthe trace 610 when compared with the VEP of the trace 600. The VEP isnoticeably improved in the trace 620 when compared with the VEP of thetrace 610. The VEP is noticeably improved in the trace 630 when comparedwith the VEP of the trace 620. However, the VEP in the trace 640 isnoticeably less than the VEP in the trace 630.

As depicted in FIG. 4A-4C, the VEP is enormously enhanced (resulting ineVEP) and optimized by using a microburst of pulses (two or more, FIG.4A) at appropriate interpulse intervals (in this case, 6.7 millisecondswas optimal for the first interpulse interval, shown in FIG. 4B) and ata inter-microburst interval (i.e., microburst frequency) thatapproximates the R-R cycle (i.e., the frequency at which the R waveportion appears in the ECG trace) of the monkey (in this case, about 0.3Hz, as shown in FIG. 4C).

The experimental results depicted in FIGS. 3D-3F and 4A-4C were obtainedusing a pulse burst including microbursts that were not synchronizedwith the cardiac cycle. In additional experiments, the effect ofsynchronizing the pulse bursts with the cardiac cycle was shown.Specifically, a single pulse was delivered at various times followingevery third R-wave. The VEP values obtained were then correlated withrespiration. With respect to synchronization with the cardiac cycle, theexperiments showed that the largest VEP was obtained when the pulse wasdelivered within 250 milliseconds after the initiation of a breath(which is accompanied by a decrease in the R-R interval). With respectto the delay period, the experiments showed that the greatestimprovement in the VEP was obtained when the pulse was delivered about400 milliseconds after the R-wave.

Additionally, the experimental data showed that by timing the pulseproperly, an improvement in efficacy on the order of a factor of ten wasobtained. Specifically, when the pulse was delivered about 0.5 secondsto about 1.0 second following the initiation of respiration and within50 milliseconds following the R-wave, the VEP had a peak-to-peakamplitude of about 0.2 mV to about 0.4 mV. In contrast, when the pulsewas delivered about 250 milliseconds after the initiation of inspirationand about 400 milliseconds following the R-wave, the VEP had apeak-to-peak amplitude of about 1.2 mV to about 1.4 mV. At maximum, thiscorresponds to about a seven-fold improvement in the VEP. These datashow that by synchronizing the stimulation with respect to thecardiorespiratory cycles of the monkey, the efficacy of the stimuluspulse can be greatly improved over that of asynchronous stimulusdelivery. These measurements were made in a monkey under deepanesthesia. Consequently, those of ordinary skill would expect an evengreater effect in an awake human.

The use of pairs of pulses is a standard physiological tool forproducing central responses by stimulation of small-diameter afferentfibers. However, according to the present invention, a pulse burstincluding microbursts of pulses having an appropriate sequence ofinterpulse intervals enormously enhances the effect of VNS. By selectingthe appropriate signal parameters (e.g., pulse width, pulse frequency,interpulse interval(s), microburst frequency, microburst duration,number of pulses in the microbursts, etc.), the exogenous electricalsignal applied to the vagus nerve may comprise a series of microburststhat each provide an eVEP.

As illustrated in FIGS. 4A and 3E, a microburst duration greater thanabout 10 milliseconds (corresponding to 4 pulses having an interpulseinterval of about 3 milliseconds.) produces a maximal eVEP in thethalamus of the monkey and an interpulse interval of about 6milliseconds to about 9 milliseconds produces maximal facilitation bythe first pulse of the second pulse. Accordingly, a brief microburst ofpulses with a total duration of about 10 milliseconds to about 20milliseconds and having an initial interpulse interval of about 6milliseconds to about 9 milliseconds and subsequent intervals of similaror longer duration may produce an optimal VEP. This is because suchmicrobursts of pulses simulate the pattern of naturally occurring actionpotentials in the small-diameter afferent vagal fibers that elicit thecentral response that the present enhanced and optimized therapy is mostinterested in evoking (see below). Selection of an appropriateinter-microburst interval to separate one microburst from the next maybe performed experimentally, although as previously noted, a period ofat least 100 milliseconds (preferably at least 500 milliseconds, andmore preferably at least one second) and at least equal to themicroburst duration may be desirable.

The most effective sequence of interpulse intervals will vary with thepatient's HRV (cardiac and respiratory timing) and also betweenindividual patients, and thus, in some embodiments, the parameters ofthe exogenous electrical signal, such as the number of pulses in amicroburst, the interpulse interval(s), the inter-microburstinterval(s), the duration of the pulse burst, the delay period(s)between each QRS wave and a microburst, the current amplitude, the QRSwaves of the cardiac cycle after which a microburst will be applied, thepulse width, and the like may be optimized for each patient. As astandard microburst sequence for initial usage, a microburst of 2 or 3pulses having an interpulse interval of about 5 milliseconds to about 10milliseconds may be used to approximate the short burst of endogenouspost-cardiac activity.

The inter-microburst interval may be determined empirically by providingmicrobursts with a steadily decreasing inter-microburst interval untilthe eVEP begins to decline. In some embodiments, the interpulse intervalvaries between the pulses. For example, the interpulse interval mayincrease between each successive pulse in the microburst, simulating thepattern of a decelerating post-synaptic potential, as illustrated inFIG. 1. In alternative embodiments, the interpulse intervals maydecrease between each successive pulse in the microburst, or may berandomly determined within a pre-selected range, e.g., about 5milliseconds to about 10 milliseconds. Alternatively, the interpulseinterval may remain constant between successive pulses in the microburst(i.e., providing a simple pulse train). Further, in a method describedbelow, the interpulse intervals may be specified between each successivepair of pulses using the VEP determined by an EEG. These modificationsto the conventional VNS methodology produce a significant enhancement ofVNS efficacy that is applicable to all VNS protocols and to manydifferent medical conditions, including disorders of the nervous system.

As noted above, the stimulation parameters (e.g., interpulseinterval(s), inter-microburst interval(s), number of pulses permicroburst, etc.) may be individually optimized for each patient. Theoptimization is accomplished by using surface electrodes to detect afar-field VEP, originating in the thalamus and other regions of theforebrain, and varying the stimulus parameters to maximize the VEPdetected. As illustrated in FIG. 5, standard EEG recording equipment 700and a 16-lead or a 25-lead electrode placement 710 of the EEG surfaceelectrodes 712, such as that typically used clinically for recordingsomatosensory or auditory evoked potentials, enables the VEP present inthe patient's forebrain to be detected, using VNS stimulus microbursttiming to synchronize averages of about 8 epochs to about 12 epochs. TheEEG recording equipment 700 may be used to produce continuous EEGwaveforms 720 and recordings 730 thereof. By testing the effects ofvarying the parameters of the exogenous electrical signal, the VEP canbe optimized for each patient.

The exogenous electrical signal used to deliver VNS is optimized inindividual patients by selecting stimulus parameters that produce thegreatest effect as measured by EEG surface electrodes 740. The pulsecurrent amplitude and pulse width is first optimized by measuring thesize of the VEP elicited by individual pulses (and not microbursts). Thenumber of pulses, interpulse intervals, and inter-microburst intervalsare then optimized (using the current amplitude and pulse widthdetermined previously) by measuring the magnitude of the VEP evoked bythe microbursts, as well as the effects on de-synchronization in thecontinuous EEG recordings. It may be desirable to determine the numberof pulses first and then determine the interpulse intervals betweenthose pulses. In alternate embodiments, it may be desirable to determinethe number of pulses first, followed by the microburst duration, andlastly, the interpulse intervals between the pulses.

Because the large eVEPs recorded in the thalamus, striatum, and insularcortex of the anesthetized monkey and shown in FIG. 4A-4C, are largeenough that if evoked in a human patient, the eVEPs are observable in astandard EEG detected using electrodes adjacent to the human patient'sscalp, the standard EEG may be used to indicate the effects ofmodifications to the signal parameters of the exogenous electricalsignal. In this manner, the EEG may be used to optimize or tune thesignal parameters of the exogenous electrical signal empirically. For ahuman patient, this method provides a safe and non-invasive way tocustomize the various signal parameters for the patient and/or thetreatment of the patient's medical condition.

The eVEP recorded in the right thalamus and right striatum issignificant for the anti-epileptic effects of VNS, whereas the eVEPrecorded in the left insular cortex is most significant for theanti-depression effects of VNS. By using regional EEG localization onthe right or left frontal electrodes, the signal parameters of theexogenous electrical signal may be optimized appropriately to achieve aneVEP in the appropriate region of the individual patient's brain.Further, the magnitude of the measured VEP may be appropriately tunedfor the patient.

The optimal exogenous electrical signal parameters for eliciting eVEPsfrom these two areas (right thalamus/striatum and left insular cortex,respectively) may differ. Both eVEPs are identifiable using known EEGrecording methods in awake human patients. Therefore, EEG recordingsmade using these methods may be used to evaluate the eVEP in theappropriate area. The EEG recording may be used to collect samples ofthe eVEP in the appropriate area(s) and those samples may be used easilyfor a parametric optimization, in a patient suffering from a disorder ofthe nervous system such as epilepsy or depression. Similarly, theexogenous electrical signal parameters used for HRV-synchronization maybe selected based on their effects on the VEP and on theheartbeat-related evoked potential both of which may be measured usingknown noninvasive EEG recording methods that use EEG electrodes attachedto the patient's scalp.

Referring to FIG. 6, an exemplary EEG is provided. A pair of traces 810and 812 correspond to the potential present in the left striatum andleft insular cortex and a pair of traces 820 and 822 correspond to thepotential present in the left striatum and left insular cortex. Whilethe same traces 810, 812, 820 and 822 depict the potential present instriatum and insular cortex, the potential in the striatum may bedistinguished from the potential in the insular cortex by its timing.Experiments have shown that pulses applied to the vagus nerve reach theparafascicular nucleus in the thalamus in about 18 milliseconds and thebasal portion of the ventral medial nucleus in about 34 milliseconds.The parafascicular nucleus then projects the stimulus to the striatumand the basal portion of the ventral medial nucleus projects thestimulus to the insular cortex. Consequently, the potential evoked bythe pulse burst in the striatum will appear in the traces 810, 812, 820and 822 before the potential evoked in the insular cortex. By analyzingthe traces 810, 812, 820 and 822, the potential inside the striatumand/or the insular cortex may be observed and the signal parameter usedto generate those potentials modified to enhance and/or optimize thosepotentials.

In FIG. 6, the strong VEP shown in traces 820 and 822 corresponding tothe right thalamus and the right striatum (or basal ganglia) isassociated with the anti-epileptic effects of VNS. As mentioned above,distinguishing the right thalamus from the right insular cortex may beaccomplished by analyzing the timing of the eVEP observed in the traces820 and 822. The strong VEP shown in traces 810 and 812 corresponding tothe left thalamus and left insular cortex is associated with theanti-depression effects of VNS. Traces 830 and 832 in the centralportion of the EEG depict a weak VEP in the thalamus. Because the EEGmethod described is non-invasive, it offers a safe and effective methodof enhancing and/or optimizing the therapeutic effects of the exogenouselectrical signal.

FIG. 7 illustrates one method of variable programming of the electricalsignal generator 200 to optimize the eVEP in the right thalamus andstriatum for epileptic patients, and in the left insula for patientssuffering from depression. As shown in FIG. 7, a computer 900 may becoupled to and used to program the computer-controlled programming wand800. The programming wand 800 may use radio frequency telemetry tocommunicate with the electrical signal generator 200 and program theburst duration, number of pulses in a microburst, interpulseinterval(s), pulse frequency, microburst duration, inter-microburstinterval, pulse width, and current amplitude of the exogenous electricalsignal delivered by the electrical signal generator 200 to the vagusnerve of the patient. Using the programming wand 800, programming may beperformed periodically or as needed on an implanted electrical signalgenerator 200. This provides the ability to continually optimize andchange the exogenous electrical signal delivered by the electricalsignal generator 200 depending on the EEG, and to respond to changestherein. Therefore, the present method of using one or more of the abovereferenced techniques, alone or in combination, significantly enhancesand/or optimizes currently available VNS therapies.

Various embodiments of the invention are described above in the DetailedDescription. While these descriptions directly describe the aboveembodiments, it is understood that those skilled in the art may conceivemodifications and/or variations to the specific embodiments shown anddescribed herein. Any such modifications or variations that fall withinthe purview of this description are intended to be included therein aswell. Unless specifically noted, it is the intention of the inventorsthat the words and phrases in the specification and claims be given theordinary and accustomed meanings to those of ordinary skill in theapplicable art(s).

The foregoing description of various embodiments of the invention knownto the applicant at this time of filing the application has beenpresented and is intended for the purposes of illustration anddescription. The present description is not intended to be exhaustivenor limit the invention to the precise form disclosed and manymodifications and variations are possible in the light of the aboveteachings. The embodiments described serve to explain the principles ofthe invention and its practical application and to enable others skilledin the art to utilize the invention in various embodiments and withvarious modifications as are suited to the particular use contemplated.Therefore, it is intended that the invention not be limited to theparticular embodiments disclosed for carrying out the invention.

While particular embodiments of the present invention have been shownand described, it will be obvious to those skilled in the art that,based upon the teachings herein, changes and modifications may be madewithout departing from this invention and its broader aspects and,therefore, the appended claims are to encompass within their scope allsuch changes and modifications as are within the true spirit and scopeof this invention. Furthermore, it is to be understood that theinvention is solely defined by the appended claims. It will beunderstood by those within the art that, in general, terms used herein,and especially in the appended claims (e.g., bodies of the appendedclaims) are generally intended as “open” terms (e.g., the term“including” should be interpreted as “including but not limited to,” theterm “having” should be interpreted as “having at least,” the term“includes” should be interpreted as “includes but is not limited to,”etc.). It will be further understood by those within the art that if aspecific number of an introduced claim recitation is intended, such anintent will be explicitly recited in the claim, and in the absence ofsuch recitation no such intent is present. For example, as an aid tounderstanding, the following appended claims may contain usage of theintroductory phrases “at least one” and “one or more” to introduce claimrecitations. However, the use of such phrases should not be construed toimply that the introduction of a claim recitation by the indefinitearticles “a” or “an” limits any particular claim containing suchintroduced claim recitation to inventions containing only one suchrecitation, even when the same claim includes the introductory phrases“one or more” or “at least one” and indefinite articles such as “a” or“an” (e.g., “a” and/or “an” should typically be interpreted to mean “atleast one” or “one or more”); the same holds true for the use ofdefinite articles used to introduce claim recitations. In addition, evenif a specific number of an introduced claim recitation is explicitlyrecited, those skilled in the art will recognize that such recitationshould typically be interpreted to mean at least the recited number(e.g., the bare recitation of “two recitations,” without othermodifiers, typically means at least two recitations, or two or morerecitations).

Accordingly, the invention is not limited except as by the appendedclaims.

The invention claimed is:
 1. A method of treating a medical condition ina patient having a brain, a vagus nerve, and a heart that generates acardiac signal having a QRS wave portion, the method comprising:identifying a select portion of the QRS wave portion of the patient'scardiac signal; after identifying the select portion of the QRS waveportion and before identifying a select portion of a next sequential QRSwave portion, generating a plurality of microbursts, each microburst ofthe plurality of microbursts being patterned and comprising 2 to 20electrical pulses, adjacent ones of the electrical pulses beingseparated from one another by an interpulse interval of less than about40 milliseconds; and delivering the plurality of microbursts directly toa selected location on the vagus nerve of the patient, the plurality ofmicrobursts delivered to the vagus nerve evoking a response in the brainof the patient, wherein sequential microbursts of the plurality ofmicrobursts are separated by at least 100 milliseconds.
 2. The method ofclaim 1, further comprising: generating additional electrical pulsesafter identifying the next sequential QRS wave portion of the cardiacsignal.
 3. The method of claim 1, further comprising: after identifyingthe select portion of the QRS wave portion, waiting a predetermineddelay period before generating the plurality of microbursts.
 4. Themethod of claim 1, wherein the electrical pulses of each microburst ofthe plurality of microbursts are generated in a series having a firstpulse and a last pulse, and wherein the interpulse interval increasessequentially along the series from the first pulse to the last pulse. 5.The method of claim 1, wherein the electrical pulses of the plurality ofmicrobursts have a pulse width ranging from about 50 microseconds toabout 1000 microseconds, and have a pulse current amplitude ranging fromabout 0.25 mA to about 8 mA.
 6. The method of claim 1, wherein theinterpulse interval was determined empirically for the patient.
 7. Themethod of claim 1, wherein the interpulse interval ranges from about 3milliseconds to about 10 milliseconds.
 8. The method of claim 1 for usewith a patient having a brain, lungs, a vagus nerve, and a heart thatgenerates a cardiac signal having a QRS wave portion, the cardiac signalalso comprising an inspiration portion corresponding to an inspirationof air by the lungs and an expiration portion corresponding to anexpiration of air by the lungs, the inspiration portion having a seriesof R wave portions, the expiration portion having a series of R waveportions, the vagus nerve evoking a vagal evoked potential in the brain,wherein: the select portion of the QRS wave portion of the patient'scardiac signal identified comprises a selected R wave portion of theinspiration portion of the cardiac signal and excludes the R waveportions of the expiration portion of the cardiac signal.
 9. The methodof claim 8, wherein the pulses of each microburst of the plurality ofmicrobursts are spaced apart to simulate endogenous afferent activityoccurring at a particular time during inspiration of air by the lungs.10. The method of claim 1, wherein the pulses of each microburst of theplurality of microbursts are spaced apart to simulate endogenousafferent activity occurring at a particular time in the cardiac signal.11. The method of claim 1, wherein the plurality of microbursts arespaced apart to simulate endogenous afferent activity occurring at aparticular time in the cardiac signal and enhance the vagal evokedpotential evoked in the brain.
 12. The method of claim 1, whereinsequential microbursts of the plurality of microbursts are separated byan interburst period ranging from about 100 milliseconds to about 10seconds.
 13. The method of claim 1, wherein sequential microbursts ofthe plurality of microbursts are separated by an interburst periodranging from about 100 milliseconds to about 6 seconds.
 14. The methodof claim 1, wherein, within at least one microburst of the plurality ofmicrobursts, at least one interpulse interval is selectively varied fromthe other interpulse intervals.
 15. A method of treating a medicalcondition in a patient that is breathing and has a brain, a vagus nerve,and a heart with a heart rate variability, the heart generating acardiac signal having a QRS wave portion, the method comprising:restricting the patient's breathing to increase the heart ratevariability; detecting a portion of the QRS wave portion of thepatient's cardiac signal; after detecting the portion of the QRS waveportion, generating a microburst comprising 2 to 20 electrical pulses;and delivering the microburst to the vagus nerve of the patient, themicroburst delivered to the vagus nerve evoking a response in the brainof the patient.
 16. A method of treating a medical condition in apatient having a brain, a vagus nerve, and a heart that generates acardiac signal having a QRS wave portion, the method comprising:identifying the QRS wave portion of the cardiac signal; afteridentifying the QRS wave portion and before identifying a nextsequential QRS wave portion, generating a plurality of microbursts, eachmicroburst of the plurality of microbursts being patterned andcomprising a series of electrical pulses, sequential electrical pulsesof each microburst being separated by an interpulse interval, the sum ofthe interpulse intervals separating the pulses of each microburst beingless than about 60 milliseconds; and delivering the plurality ofmicrobursts directly to a selected location on the vagus nerve of thepatient, the plurality of microbursts delivered to the vagus nerveevoking a response in the brain of the patient, wherein sequentialmicrobursts of the plurality of microbursts are separated by at least100 milliseconds.
 17. The method of claim 16, further comprising: afteridentifying the QRS wave portion, waiting a predetermined delay periodbefore applying the plurality of microbursts to the vagus nerve.
 18. Themethod of claim 16, further comprising: after identifying the QRS waveportion, waiting less than about 500 milliseconds before applying themicroburst plurality of microbursts to the vagus nerve.
 19. The methodof claim 16, wherein the electrical pulses of each microburst of theplurality of microbursts have a pulse width ranging from about 50microseconds to about 1000 microseconds.
 20. The method of claim 16,wherein each of the interpulse intervals is less than about 40milliseconds.
 21. The method of claim 16, wherein each of the interpulseintervals is determined empirically for the patient.
 22. The method ofclaim 16, wherein each of the interpulse intervals ranges from about 3milliseconds to about 12 milliseconds.
 23. A method of treating amedical condition in a patient that is breathing and has a brain, avagus nerve, and a heart with a heart rate variability, a heartgenerating a cardiac signal having a QRS wave portion, the methodcomprising: restricting the patient's breathing to increase the heartrate variability; detecting the QRS wave portion of the cardiac signal;generating a microburst comprising a series electrical pulses separatedby an interpulse interval, the sum of the interpulse intervalsseparating the pulses being less than 60 milliseconds; and deliveringthe microburst to the vagus nerve of the patient, the microburstdelivered to the vagus nerve evoking a response in the brain of thepatient.
 24. A system for treating a medical condition in a patienthaving a brain, a vagus nerve, and a heart that generates a cardiacsignal having a QRS wave portion, the system comprising: a communicationinterface configured to receive at least a select portion of the QRSwave portion of the cardiac signal; an electrical signal generatorconfigured to generate a plurality of microbursts after the receipt ofthe select portion of the QRS wave portion by the communicationinterface and before receiving a select portion of a next sequential QRSwave portion by the communication interface, each microburst of theplurality of microbursts being patterned, comprising a series ofelectrical pulses, and having a duration of less than about one second,adjacent ones of the electrical pulses of each microburst beingseparated from one another by an interpulse interval of less than about40 milliseconds, sequential microbursts of the plurality of microburstsbeing separated by at least 100 milliseconds; and an electrode inelectrical communication with the vagus nerve, the electrode beingconfigured to deliver the plurality of microbursts to a select locationon the vagus nerve of the patient, the plurality of microburstsdelivered to the vagus nerve evoking a response in the brain of thepatient.
 25. The system of claim 24, wherein the duration of eachmicroburst of the plurality of microbursts is less than about 100milliseconds.
 26. The system of claim 24, wherein the electrical signalgenerator is configured to wait a predetermined delay period afterreceipt of the select portion of the QRS wave portion wave beforeapplying the plurality of microbursts.
 27. The system of claim 24,wherein the interpulse interval between adjacent ones of the electricalpulses ranges from about 3 milliseconds to about 10 milliseconds.
 28. Anon-transitory computer readable medium having computer executablecomponents for identifying a QRS wave portion of a cardiac cycle; afteridentifying a first QRS wave portion of the cardiac cycle and beforeidentifying a next sequential QRS wave portion of the cardiac cycle,generating a plurality of microbursts, each microburst of the pluralityof microbursts being patterned and having 2 to 20 electrical pulses,adjacent ones of the electrical pulses being separated from one anotherby an interpulse interval of less than about 40 milliseconds; anddelivering the plurality of microbursts via an electrode to a selectlocation on the vagus nerve of a patient, the plurality of microburstsdelivered to the vagus nerve evoking a response in a brain of thepatient, wherein sequential microbursts of the plurality of microburstsare separated by at least 100 milliseconds.
 29. The computer readablemedium of claim 28, wherein the computer readable medium furthercomprises computer executable components for determining the duration ofeach of the interpulse intervals.
 30. A method of maximizing a vagalevoked potential (VEP) in a patient having a brain, a vagus nerve, and aheart that generates a cardiac signal having a QRS wave portion, themethod comprising: identifying a select portion of the QRS wave portionof the patient's cardiac signal; after identifying the select portion ofthe QRS wave portion and before identifying a select portion of a nextsequential QRS wave portion, generating a plurality of microbursts, eachmicroburst of the plurality of microbursts being patterned andcomprising a plurality of electrical pulses, adjacent ones of theelectrical pulses being separated from one another by an interpulseinterval of less than about 40 milliseconds; and delivering theplurality of microbursts directly to a selected location on the vagusnerve of the patient, the plurality of microbursts delivered to thevagus nerve evoking a response in the brain of the patient, whereinsequential microbursts of the plurality of microbursts are separated byan interburst interval of at least 100 milliseconds, and wherein, withinat least one microburst of the plurality of microbursts, at least oneinterpulse interval is selectively varied from the other interpulseintervals.
 31. The method of claim 30, wherein, within at least onemicroburst of the plurality of microbursts, the interpulse interval isincreased between successive pulses of the plurality of pulses.
 32. Themethod of claim 30, wherein, within at least one microburst of theplurality of microbursts, the interpulse interval is decreased betweensuccessive pulses of the plurality of pulses.
 33. The method of claim30, wherein, within at least one microburst of the plurality ofmicrobursts, the interpulse interval is randomly determined within apre-selected range.
 34. The method of claim 33, wherein the pre-selectedrange ranges from about 5 milliseconds to about 10 milliseconds.
 35. Themethod of claim 30, wherein at least one of the interpulse interval, theinterburst interval, and the number of pulses within each respectivemicroburst are selectively varied to optimize stimulation of thepatient.